Glutamate receptors are roughly categorized into two types, namely, ionotropic type (iGluR) and metabotropic type (mGluR). The receptors of ionotropic type (iGluR) are further categorized into NMDA (N-methyl-D-aspartic acid) type and non-NMDA type [Jpn. J. Neuropsychopharmacol., 18(5), 345-365 (1996)].
When NMDA receptors are activated with agonists, they introduce calcium ions (Ca.sup.2+) into cells to increase the intracellular Ca.sup.2+ concentration. In the cells, accordingly, various Ca.sup.2+ -dependent enzymes are activated to cause a chain of cellular changes. If the cellular changes proceed over a certain threshold value, the cell is presumed to lose irreversibly its life [Folia Pharmacol. Jpn., No. 104, 177-187 (1994)].
The metabotropic L-glutamate receptors (mGluR) are classified into three groups (Groups-I, -II and -III) based on their sequence homology, intracellular signal transduction pathway, and selectivity of agonists for receptor sub-types. A typical example of the agonist for Group-I is quisqualic acid, which promotes formation of inositol triphosphate (IP.sub.3) and variations of intracellular Ca.sup.2+ dynamics.
The agonists for Group-II and Group-III inhibit intracellular CAMP formation induced by forskolin. In the agonist selectivity, the mGluR of Group-II differs from that of Group-III.
Examples of the agonists for mGluR of Group-II include DCG-IV [(2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine] and L-CCG-I [(2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine]. Examples of the agonists for mGlu R of Group-III include L-AP4 [L-2-amino-4-phosphonobutyric acid] [Japanese Patent Provisional Publications No. 6(1994)-256323 and No. 6(1994)-24970, and Jpn. J. Neuropsychopharmacol., 18(6), 419-425 (1996)].
The agonists for mGluR of Group-II are known to inhibit release of transmitter at synapses, and consequently to lower the efficiency of synaptic conduction. If the synaptic transmission efficiency is lowered in the central nervous system, the muscles in the kinetic system are presumed to be relaxed. Actually, it has been ascertained by experiments on animals that the agonists for mGluR of Group-II remarkably potentiate anesthesia. These agonists are also known to give sedation (or tranquilizer-like) effect and anti-epileptic effect. Further, since these agonists can protect the neurons cells from death in vivo and in vitro caused by excitatory amino acids, they are expected to be used as neuron protectors. Since the agonists for mGluR of Group-II are utterly new agonists for glutamate receptors and seem to be indispensable for pharmaceutical studies of the central nervous system, they are of great value as reagents for the laboratory study. [Folia Pharmacol. Jpn., No. 104, 177-187 (1994)].
DCG-IV (which is one of the known agonists for mGluR of Group-II) strongly activates the mGluR, and is hence expected to act as a neuron protector. However, since DCG-IV also activates NMDA receptors (which are presumed to be concerned with cell death caused by excitatory amino acids), it is desired to develop a new agonist for mGluR having no NMDA activating component.